Germline mutations in <i>Protection of Telomeres 1</i> in two families with Hodgkin lymphoma

McMaster, Mary L.; Sun, Chang; Landi, Maria Teresa; Savage, Sharon A.; Rotunno, Melissa; Yang, Xiaohong R.; Jones, Kristine; Vogt, Aurélie; Hutchinson, Amy; Zhu, Bin; Wang, Mingyi; Hicks, Belynda; Thirunavukarason, Anand; Stewart, Douglas R.; Koutros, Stella; Goldstein, Alisa M.; Chanock, Stephen J.; Caporaso, Neil E.; Tucker, Margaret A.; Goldin, Lynn R.; Liu, Yie

doi:10.1111/bjh.15203

Cited by 48 publications

(59 citation statements)

References 14 publications

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“…67); and Hodgkin lymphoma (5%, 2 of 41 families; ref. 68). These are generally loss-of-function mutations and are predicted to cause telomere lengthening.…”

Section: The Human Short Telomere Syndrome Phenotypementioning

confidence: 99%

Long telomeres and cancer risk: the price of cellular immortality

McNally¹,

Luncsford²,

Armanios³

2019

Journal of Clinical Investigation

122

119

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“…67); and Hodgkin lymphoma (5%, 2 of 41 families; ref. 68). These are generally loss-of-function mutations and are predicted to cause telomere lengthening.…”

Section: The Human Short Telomere Syndrome Phenotypementioning

confidence: 99%

Long telomeres and cancer risk: the price of cellular immortality

McNally¹,

Luncsford²,

Armanios³

2019

Journal of Clinical Investigation

122

119

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“…In our study, we have attempted to interpret a selection of non-coding variants using in silico and bioinformatic tools, however, the adequate analysis of intronic and intergenic variants remains a challenge. There are several reports of WGS being successfully implemented to implicate rare, high-penetrance germline variants in cancer, for example POT1 mutations in familial melanoma and Hodgkin lymphoma (Mcmaster et al, 2018;Wong et al, 2019) and POLE and POLD1 mutations in colorectal adenomas or carcinomas (Palles et al, 2013). In a previous study, we have used our pipeline (FCVPPv2) to prioritize novel variants in non-medullary thyroid cancer prone families (Srivastava et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…An association between various HLA class I and class II alleles and increased risk of HL has been reported (Diepstra et al, 2005), while other non-HLA susceptibility loci have been detected through genome-wide association studies (Frampton et al, 2013;Cozen et al, 2014;Kushekhar et al, 2014). The identification of major predisposing genes is a more daunting task, however, rare germline variants in KLDHC8B, NPAT, ACAN, KDR, DICER1, and POT1 gene have been reported by different groups in high-risk HL families (Salipante et al, 2009;Saarinen et al, 2011;Ristolainen et al, 2015;Rotunno et al, 2016;Bandapalli et al, 2018;Mcmaster et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Identification of Familial Hodgkin Lymphoma Predisposing Genes Using Whole Genome Sequencing

Srivastava

Galimberti

Kumar

et al. 2020

Front. Bioeng. Biotechnol.

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Hodgkin lymphoma (HL) is a lymphoproliferative malignancy of B-cell origin that accounts for 10% of all lymphomas. Despite evidence suggesting strong familial clustering of HL, there is no clear understanding of the contribution of genes predisposing to HL. In this study, whole genome sequencing (WGS) was performed on 7 affected and 9 unaffected family members from three HL-prone families and variants were prioritized using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). WGS identified a total of 98,564, 170,550, and 113,654 variants which were reduced by pedigree-based filtering to 18,158, 465, and 26,465 in families I, II, and III, respectively. In addition to variants affecting amino acid sequences, variants in promoters, enhancers, transcription factors binding sites, and microRNA seed sequences were identified from upstream, downstream, 5 ′ and 3 ′ untranslated regions. A panel of 565 cancer predisposing and other cancer-related genes and of 2,383 potential candidate HL genes were also screened in these families to aid further prioritization. Pathway analysis of segregating genes with Combined Annotation Dependent Depletion Tool (CADD) scores >20 was performed using Ingenuity Pathway Analysis software which implicated several candidate genes in pathways involved in B-cell activation and proliferation and in the network of "Cancer, Hematological disease and Immunological Disease." We used the FCVPPv2 for further in silico analyses and prioritized 45 coding and 79 non-coding variants from the three families. Further literature-based analysis allowed us to constrict this list to one rare germline variant each in families I and II and two in family III. Functional studies were conducted on the candidate from family I in a previous study, resulting in the identification and functional validation of a novel heterozygous missense variant in the tumor suppressor gene DICER1 as potential HL predisposition factor. We aim to identify the individual genes responsible for predisposition in the remaining two families and will functionally validate these in further studies.

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“…Sequencing of cancer genomes identified POT1 mutations in several solid tumors and hematological malignancies (Quesada et al 2011;Lazzerini-Denchi and Sfeir 2016;Speedy et al 2016;McMaster et al 2018) . To better understand the basis by which mutant POT1 alleles foster tumorigenesis, we performed a genome-wide CRISPRi screen.…”

Section: Replication Stress As a Major Vulnerability In Cells With Mumentioning

confidence: 99%

Telomere relocalization to the nuclear pore complex in response to replication stress

Pinzaru¹,

Lamm

al-Kareh³

et al. 2020

Preprint

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Mutations in the telomere binding protein, POT1 are associated with solid tumors and leukemias. POT1 alterations cause rapid telomere elongation, ATR kinase activation, telomere fragility, and accelerated tumor development. Here, we investigated the impact of mutant POT1 alleles through complementary genetic and proteomic approaches based on CRISPR-interference and biotinbased proximity labelling, respectively. These screens revealed that replication stress is a major vulnerability in cells expressing mutant POT1 and manifest in increased mitotic DNA synthesis (MiDAS) at telomeres. Our study also unveiled a role for the nuclear pore complex (NPC) in resolving replication defects at telomeres. Depletion of NPC subunits in the context of POT1 dysfunction increased DNA damage signaling and telomere fragility. Furthermore, we observed telomere repositioning to the nuclear periphery driven by nuclear F-actin polymerization in cells with POT1 mutations. In conclusion, our study establishes that relocalization of dysfunctional telomeres to the nuclear periphery is critical to preserve telomere repeat integrity.3 Introduction:

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Germline mutations in Protection of Telomeres 1 in two families with Hodgkin lymphoma

Cited by 48 publications

References 14 publications

Long telomeres and cancer risk: the price of cellular immortality

Long telomeres and cancer risk: the price of cellular immortality

Identification of Familial Hodgkin Lymphoma Predisposing Genes Using Whole Genome Sequencing

Telomere relocalization to the nuclear pore complex in response to replication stress

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